Highlights
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REAC-TAVI 2 will study the effects of aspirin vs. low-dose ticagrelor post-TAVI.
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The study will randomize patients with high ischemic risk post-TAVI to aspirin vs. ticagrelor.
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REAC-TAVI 2 will assess subclinical valve thrombosis at 3 and 12 months after TAVI.
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All bleeding events at 12 months post-TAVI will be assessed according to BARC criteria.
ABSTRACT
Background
Patients undergoing transcatheter aortic valve implantation (TAVI) frequently experience life-threatening ischemic and bleeding complications. However, management of antithrombotic therapy after TAVI in patients without oral anticoagulation (OAC), particularly in patients with high burden for subsequent ischemic events, has limited evidence from randomized controlled trials.
Methods
The REAC TAVI2 trial is a prospective, multicenter, open-label, phase III randomized trial (NCT05283356). A total of 1206 patients undergoing TAVI with high ischemic risk (defined as concomitant coronary artery disease, diabetes mellitus or peripheral vascular disease) will be randomized in a 1:1 ratio to single antiplatelet therapy with aspirin (100 mg once daily) or low-dose ticagrelor (60 mg twice daily). The primary endpoint is the incidence of a net adverse clinical event (NACE) at 1-year after TAVI. NACE is defined as a composite of all-cause mortality, cerebrovascular events, myocardial infarction, progressive angina leading to emergency evaluation, rehospitalization or new coronary angiogram, clinical valve thrombosis, acute limb ischemia leading to hospitalization, and type 2, 3, or 5 bleeding. The secondary endpoint is the incidence of subclinical valve thrombosis detected by hypo-attenuated leaflet thickening and reduced leaflet motion at 3 and 12 months post-TAVI assessed by 4-dimensional computed tomography.
Summary
In patients undergoing TAVI without an indication for OAC, there is a need for antiplatelet therapy that provides protection against ischemic events without increasing bleeding, particularly in the subset of patients at heightened risk of ischemic events. The REAC-TAVI 2 is a randomized multicenter clinical trial designed to study the effect of single antiplatelet therapy with aspirin compared to low-dose ticagrelor on a composite outcome of all-cause mortality, ischemic, and bleeding events after TAVI.
Background
Transcatheter aortic valve implantation (TAVI) has recently expanded to include patients with severe tricuspid aortic stenosis (AS) across all surgical risks. In the early phases of TAVI, bleeding complications were relatively frequent and remained relevant due to the associated mortality risk. However, the refinement in TAVI techniques and devices and after the ARTE and POPular TAVI chancing the recommendation of double to single antiplatelet therapy, the incidence of periprocedural bleeding has decreased significantly. ,, With TAVI expanding to younger patients with lower hemorrhagic risk and greater life expectancy, the risk of future ischemic events becomes more important, ,, especially in patients with higher large ischemic burden such as diabetes mellitus (DM), coronary artery disease (CAD) or peripheral vascular disease (PVD). Prior studies have shown high rates of residual platelet reactivity with clopidogrel in patients undergoing TAVI, a marker of thrombotic risk, during the periprocedural period, which can persist for up to 3 months postprocedure. Ticagrelor on the contrary is associated with more potent and predictable P2Y 12 inhibitory effects compared with clopidogrel. Several investigations in patients undergoing coronary interventions have shown the favorable safety and efficacy profiles of ticagrelor monotherapy. Nevertheless, there is limited data on how single antiplatelet therapy (SAPT) with aspirin vs ticagrelor compare in patients undergoing TAVI. We therefore propose a prospective, randomized clinical trial comparing aspirin vs low-dose ticagrelor 60 mg in a population of patients undergoing elective TAVI with a high ischemic risk, defined as coexisting DM, CAD, or PVD.
Methods
Study design
The REAC-TAVI 2 (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) is a prospective, multicenter, open/label, superiority phase III randomized clinical trial. The study will test the safety and efficacy of SAPT regimen regarding clinical outcomes, bioprosthetic performance, and leaflet thrombosis in patients undergoing successful TAVI for symptomatic severe AS without an indication for oral anticoagulation (OAC) who are at high-risk of ischemic events. A total of 1,206 patients will be included and randomized to aspirin (100 mg once daily) or ticagrelor (60 mg twice daily) in a 1:1 ratio. The trial protocol has been registered at ClinicalTrials.gov (NCT05283356) and at the European Clinical Trials Database (EUDRACT 2021-003927-13). The trial will be conducted in more than 25 centers in up to 4 countries (Spain, Nederland, Italy and Portugal).
Study population
Patients aged 18 years or older diagnosed with degenerative, symptomatic severe tricuspid AS or degenerated bioprosthesis, along with concomitant DM, CAD, or PVD, who are scheduled for TAVI are potentially eligible to participate in the study. While transfemoral access is the preferred approach for TAVI procedures in this study, alternative access routes may also be performed when decided by the Heart Team if deemed necessary based on individual patient anatomy and clinical considerations. All access routes and vascular closure used will be documented and reported in the study. Severe AS is defined by the most recent ESC guidelines. Prior CAD is defined as a history of ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), stable angina, or other documented events, confirmed by invasive or noninvasive ischemia screening tests or imaging studies. DM is defined as the latest World Health Organization diagnostic criteria, and PVD (brain, carotid, renal, aorto-iliac-femoral, distal vessels of the upper and lower extremities) is defined as prior peripheral arterial disease documented by clinical history, invasive or noninvasive ischemia screening tests or imaging study. Successful TAVI procedure is defined as implantation of the a single transcatheter heart valve in the correct position without major procedural complications (technical success according to VARC-3 criteria). Exclusion criteria encompass patients on OAC, patients who are unable to transition to SAPT post-TAVI, patients undergoing TAVI solely for pure aortic insufficiency, those with a history of overt major bleeding or intracranial hemorrhage, and history of ischemic stroke within the 30 days preceding the TAVI procedure. The detailed inclusion and exclusion criteria are presented in Table 1 .
Table 1
Inclusion and exclusion criteria of the REAC-TAVI 2
| Inclusion |
|---|
| 1) Provision of informed consent prior to any study specific procedures. |
| 2) Adult patients (≥18 years) with ability to understand and accept the participation in the clinical trial. |
|
3) Patients with degenerative symptomatic severe AS accepted for TAVI with any commercially approved TAVI devices, after evaluation by the Heart Team of each center, and with at least one of the following comorbidities:
•Diabetes Mellitus, adhering to current WHO diagnostic criteria: fasting plasma glucose ≥ 7.0 mmol/L or 2-hour plasma glucose ≥ 11.1 mmol/L, or under treatment with an oral hypoglycemic agent or insulin. •Prior coronary artery disease (STEMI, NSTEMI, stable angina, or others) documented by invasive or noninvasive ischemia screening tests or imaging studies. •Prior peripheral arterial disease (brain, carotid, renal, aorto-iliac-femoral, distal vessels of the upper and lower extremities) documented by clinical history, invasive or noninvasive ischemia screening tests or imaging study. |
| 4) Successful TAVI performed by any vascular access, defined as technical success according to VARC-3 criteria. |
| 5) Patients who are not participating in any other clinical trial or research study (registries allowed). |
| Exclusion |
| 1) Patients under chronic OAC for any specific pathology. |
| 2) Patients that cannot undergo a regimen of SAPT after TAVI. |
| 3) Active pathological bleeding. |
| 4) History of overt major bleeding or intracranial hemorrhage. |
| 5) History of ischemic stroke within the last thirty days prior TAVI. |
| 6) Patients with severe hepatic insufficiency. |
| 7) Concomitant oral or intravenous therapy with potent inhibitors of cytochrome P450 3A (CYP3A) that cannot be suspended during the study. |
| 8) Known pregnancy, breast-feeding, or intend to become pregnant during the study period. |
| 9) History of allergic reactions or intolerance to Ticagrelor or Aspirin or any of the excipients. |
| 10) Patients who cannot attend follow-up visits scheduled in the study. |
AS, Aortic Stenosis; ASA, Acetylsalicylic Acid; CAD, Coronary Artery Disease; DM, Diabetes Mellitus; NSTEMI, Non-ST-elevation Myocardial Infarction; OAC, Oral Anticoagulation; PAD, Peripheral Artery Disease; SAPT, Single Anti Platelet Therapy; STEMI, ST-elevation Myocardial Infarction; TAVI, Transcatheter Aortic Valve Implantation.
The study started in 2023 and will continue until a total of 1,206 patients have been included and followed for 1 year. As of August 2025, a total of 642 patients have been successfully recruited across 19 sites in Spain. The study has received regulatory approval in Italy and Portugal, while in the Netherlands, the approval process is still pending. End of enrolment is anticipated in the third quarter of 2026. Considering the required 1-year follow-up period, the results of the REACT-TAVI 2 trial are expected to be presented in late 2027.
Study procedures, treatment and follow-up
A randomization list will be generated using the SAS 9 software [version 9.0] for Windows. After written informed consent is signed and screening is performed, patients will be randomized prior to TAVI or within the first 24 hours after TAVI. Patients will be randomized between the active comparator group (ASA 100mg per day) or the experimental group (ticagrelor 60mg twice a day) using the REDCap electronic case report form (eCRF) randomization module in a 1:1 ratio to achieve balanced randomization across treatment groups ( Figure ). TAVI will be performed using standard techniques as described in the literature. The indication for TAVI, selection of transcatheter heart valve type, and valve sizing will be determined by the multidisciplinary heart team at each participating center, in accordance with local protocols and best clinical practice. Patients with bicuspid valves will not be specifically excluded in the trial. Patients received intravenous heparin according to the center’s usual practice until an ACT of 250 is reached, with additional doses if the activated clotting time was <250s. Time and date of first dose of both treatment groups will be recorded. Both treatment groups will start the assigned treatment within 24 hours after successful TAVI and after ensuring the absence of any relevant complications. There will be no pretreatment or loading dose for any of the study medications. The treatment duration will be 12 months following TAVI in both groups. Thereafter, antiplatelet regimen will be at physician discretion. The nonantithrombotic treatment will be left by the attending physician according to current and standard clinical practice. Endpoint events and adverse events will continue to be recorded during hospitalization.
Flow chart for the REAC-TAVI 2 trial. 4D-CT, 4-dimensional Computed Tomography; AS, Aortic Stenosis; ASA, Acetylsalicylic acid; NACE, Net Adverse Clinical Event; OAC, Oral Anticoagulation; SAPT, Single Antiplatelet Therapy; TAVI, Transcatheter Aortic Valve Implantation; TTE, Transthoracic Echocardiogram.
The study protocol incorporates 2 follow-up visits: a clinical and echocardiography assessment at 90 and 365 days post-TAVI. Phone calls and medical record review are also permitted during the whole follow-up with a particular focus on cardiovascular outcomes and adverse events. All clinical events related to the primary objective will be entered into the eCRF and evaluated by the Clinical Event Committee (CEC) for adjudication. In a sub-group of patients from selected centers, these visits will be accompanied by valve thrombosis assessment by performing a 4-dimensional computed tomography (4D-CT) at 90 and 365 days post-TAVI. An overview of data collected during screening, enrolment, and follow-up visits is depicted in Table 2 .
Table 2
Study chart of data collected during screening, enrolment and the treatment follow-up period
| Admission | Post-TAVI | Follow-up | |||
|---|---|---|---|---|---|
| Screening | Enrolment | In-hospital | 3 months | 12 months | |
| Eligibility screening | X | ||||
| Informed consent | X | ||||
| Randomization † | X | X | |||
| Demographic | X | ||||
| Medical and medication history | X | ||||
| TAVI details | X | ||||
| Physical examination | X | X | X | X | |
| EKG | X | X | X * | X | |
| Transthoracic echocardiogram | X | X | X * | X | |
| Laboratory data | X | X | |||
| 4D-CT imaging at prespecified centers | X | X | |||
| NACE | X | X | X | X | |
| AE assessment | X | X | X | X | |
| SAE assessment | X | X | X | X | |
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